CN1217938C - Bis-arylsulfones - Google Patents

Bis-arylsulfones Download PDF

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CN1217938C
CN1217938C CN01810679XA CN01810679A CN1217938C CN 1217938 C CN1217938 C CN 1217938C CN 01810679X A CN01810679X A CN 01810679XA CN 01810679 A CN01810679 A CN 01810679A CN 1217938 C CN1217938 C CN 1217938C
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phenyl
sulfonyl
diazesuberane
compound
base
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CN1433407A (en
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E·J·雅克布森
S·J·金
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Pharmacia and Upjohn Co
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Abstract

The present invention provides pharmaceutically active compounds useful for the treatment of diseases or disorders of the central nervous system.

Description

Bis-arylsulfones
In relation to the cross reference applied
According to 35 USC 119 (e) (i), this application claims the interests of following provisional application: the 6/20/00 U.S.Serial No.60/212 submitted, 894, the 9/29/00 U.S.Serial No.60/237 submitted, 025, the 10/12/00 U.S.Serial No.60/239 submitted, the 713 and 2/13/01 U.S.Serial No.60/268 submitted, 261.
Invention field
The present invention relates to novel bis-arylsulfone derivatives, more particularly, to the bis-arylsulfones compound of following formula I.These compounds are 5-HT receptors ligands, can be used for treatment and wherein need to adjust the active disease of 5-HT.
Background of invention
Thrombocytin has involved the disease and illness for largely rising in central nervous system.They include being related to sleep, diet, feels pain, control body temperature, control blood pressure, depression and anxiety, the disease and illness of schizophrenia and other physical conditions.Thrombocytin is also played an important role in peripheral-system, such as gastronintestinal system, it has been found that it mediates various contractions, secretion and electro physiology effect.
It is widely distributed in vivo as thrombocytin as a result, in the presence of to influence serotonergic systems drug huge concern.Exactly, agonist, partial agonist and antagonist are the vomitings including anxiety, depression, hypertension, migraine, obesity, compulsive disorder, schizophrenia, autism, neurodegeneration obstacle (such as Alzheimer's disease, Parkinson's syndrome and hungtington's chorea) and phase chemotherapy induced where the interest for treating extensive obstacle.
Main species (the 5-HT of serotonin receptor1-7) the independent receptor of Official Classification is had already passed through containing 14 to 18 kinds.Referring to Glennon etc., Neuroscience and BehavioralReviews (Neuscience and behavior are commented on), 1990,14,35；D.Hoyer, etc. Pharmacol.Rev. (pharmacological review) 1994,46,157-203.
It needs to can be used for treating the pharmaceutical agent with 5-HT receptor related disease and illness at present.Exactly, it is desirable to be able to the reagent (such as receptor-specific agonists or antagonist) of each receptor subtype of selective binding；Such reagent as pharmaceutical agent will be it is useful, the research that can be used for promoting 5-HT receptor family or facilitate perhaps is identified to the compound of the specific 5-HT receptor of other selective bindings.
For example, 1993 authenticated 5-HT6Receptor (Monsma etc., Mol.Pharmacol. (molecular pharmacology) 1993,43,320-327 and Ruat, M. etc., Biochem.Biophys.Res.Com. (molecular chemistry and biophysical studies communicate) 1993,193,269-276).Combine 5-HT to several antidepressants and atypical major tranquilizer high-affinity6Receptor, this combination can be factor (Roth etc., J.Pharm.Exp.Therapeut. (pharmacology and experimental therapeutic magazine) 1994,268,1403-1410 in its activity；Sleight etc., Exp.Opin.Ther.Patents 1998,8,1217-1224；Bourson etc., Brit.J.Pharm. (Britain's pharmacology magazine) 1998,125,1562-1566；Boess etc., Mol.Pharmacol. (molecular pharmacology) 1998,54,577-583；Sleight etc., Brit.J.Pharmacol. (Britain's pharmacology magazine) 1998,124,556-562).In addition, 5-HT6Receptor is related (Yoshioka etc., Life Sciences (life science) 1998,17/18,1473-1477) with generalization stress and anxiety state.These researchs and observation prompt together, antagonism 5-HT6The compound of receptor will can be used for treating the obstacle of central nervous system.
In general, the compounds of this invention is 5-HT ligand.Exactly, they being capable of selective binding 5-HT6Receptor (such as receptor-specific agonists or antagonist).Therefore, they, which can be used for treating, wherein needs to adjust 5-HT activity, particularly 5-HT6Active disease.Therefore, the compound of the present invention can be used for treating the disease or obstacle of central nervous system.More particularly for treatment mental disease, dementia paranoides, psychotic depression, mania, schizophrenia, schizophreniform disorder, anxiety, migraine, drug habit, convulsive disorders, personality disorder, post traumatic stress syndrome, alcoholism, panic attack, besetment and behavior disorder and sleep disturbance.The compound of the present invention can also be used in the cone extracorporeal movement side effect for treating schizoid spirit, emotion, vegetalitas and psychomotor symptoms and other antipsychotics.A kind of finally effect will allow the major tranquilizer using higher doses, therefore obtain bigger antipsychotic effect as the result for reducing side effect.The compound of the present invention can also be used to adjust dietary behavior, therefore can be used for treating overweight and related morbidity and death.
Information discloses
United States Patent (USP) No.5,627,077 discloses the aniline compound that can be used for preparing mineral oil.
United States Patent (USP) No.4,851,423 discloses antiviral and anti-inflammatory pharmaceutical active compounds.
PCT international publication WO 99/37623 discloses the compounds with pharmacological activity, for treating CNS obstacle.
PCT international publication WO 99/47516 discloses 3- (2- pyrrolidinylmethyl)-benzazolyl compounds with 5-HT6 compatibility.
PCT international publication WO 99/42465 discloses the novel sulphonamide derivatives with CNS activity.
PCT international publication WO 99/02502 discloses the compounds with pharmacological activity, for treating CNS obstacle.
PCT international publication WO 93/17682 discloses angiotensin II receptor antagonist.
PCT international publication WO 92/06683 discloses the pharmaceutical composition with anti-retrovirus activity.
PCT international publication WO 92/20642 discloses the double or single aryl bicyclics and/or heteroaryl compound of performance protein tyrosine kinase inhibitory activity.
The abstract of PCT international publication WO 92/9408956A discloses the compound that can be used for reducing blood lipid level.
The abstract of JO 3056-431-a is disclosed with analgesic, anti-inflammatory, antirheumatic and the active diphenyl compounds of anti-nephrosis.
The abstract of JP 07033735-A discloses the diphenyl sulfone compound that can be used for treating inflammation, allergy and asthma.
The abstract of WO 9318035 discloses the angiotensin-ii receptor containing annelated heterocycles and two benzyl rings.
The abstract of WO 9707790 discloses the compound containing diphenyl, for treating infectious disease, such as malaria.
Summary of the invention
The present invention provides novel compound of formula I:
Or its pharmaceutically acceptable salt, wherein
R1It is H, C1-12Alkyl, C1-6Alkylaryl or aryl；Each R2It is independently H, C1-12Alkyl, C1-12Alkenyl, halogen, NO2、CN、CF3Or OR1；Each R3It is independently H, C1-12Alkyl, C1-12Alkenyl or R4；R4It is halogen, NO2、CN、CF3、OR1、CONR1R1、NHSO2R1、NR1R1、NR1COR1、SO2NR1R1, C (=O) R1、CO2R1Or S (O)iR1；Each R5It is independently H, C1-5Alkyl, C1-6Alkylaryl, aryl, C (=O) R1、S(O)2R1、C(O)NR1R1、CO2R1Or CSR1；At each occurrence, alkyl, alkenyl, alkylaryl or aryl are optionally by one or more R4Replace；
I is 0,1 or 2；M is 1,2 or 3；N is 1,2,3,4 or 5.
The present invention further provides novel Formula II compounds:
Figure C0181067900112
Or its pharmaceutically acceptable salt, wherein
R6It is H or C1-4Alkyl；R7It is H, halogen, C1-4Alkyl or NR6R6；R8It is H, halogen or C1-4Alkyl；With；Each R9It is independently H, C1-4Alkyl, C (=O) R10、S(O)2R10、C(O)NR10R10、CO2R10Or CSR10；And each R10It is independently H, C1-12Alkyl, C1-6Alkylaryl or aryl.
The present invention further provides pharmaceutical compositions, include Formulas I or II compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.In a preferred embodiment, composition preferably comprises the compound of formula I or its pharmaceutically acceptable salt of therapeutically effective amount.
The present invention further provides the methods for treating mammalian diseases or illness, wherein involving 5-HT receptor, and need to adjust 5-HT function, and this method includes to give the mammal formula III compound of therapeutically effective amount
Or its pharmaceutically acceptable salt, wherein
R1It is H, C1-12Alkyl, C1-6Alkylaryl or aryl；Each R2It is independently H, C1-12Alkyl, C1-12Alkenyl, halogen, NO2、CN、CF3Or OR1；Each R3It is independently H, C1-12Alkyl, C1-12Alkenyl or R4；R4It is halogen, NO2、CN、CF3、OR1、CONR1R1、NHSO2R1、NR1R1、NR1COR1、SO2NR1R1, C (=O) R1、CO2R1Or S (O)iR1；Each R5It is independently H, C1-6Alkyl, C1-6Alkylaryl, aryl, C (=O) R1、S(O)2R1、C(O)NR1R1、CO2R1Or CSR1；At each occurrence, alkyl, alkenyl, alkylaryl or aryl are optionally by one or more R4Replace；K is 1 or 2；I is 0,1 or 2；M is 1,2 or 3；N is 1,2,3,4 or 5.
The present invention further provides the methods for treating mammalian diseases or illness, wherein involving 5-HT6Receptor, and need to adjust 5-HT6Function, this method include to give the mammal formula III compound or its pharmaceutically acceptable salt of therapeutically effective amount.
The present invention further provides the methods for treating or preventing central nervous system disease or obstacle, formula III compound or its pharmaceutically acceptable salt comprising giving mammal therapeutically effective amount.Compound of formula I is including but not limited to following to its active disease or obstacle: fat, depression, schizophrenia, schizophreniform disorder, Schizoaffective phrenoblabia, delusional disorder, with nervous related disease (such as generalized anxiety disorder), panic disorder, it is terrified, besetment and behavior disorder, post traumatic stress syndrome, immune system depression, major depression, the uropoiesis that stress induces, stomach and intestine or cardiovascular system problem (such as stress incontinence), neurodegeneration obstacle, autism, the vomiting of phase chemotherapy induced, hypertension, migraine, cluster headache, the sexual dysfunction of mammal (such as people), assuetude disturbance and abstinence syndrome, adjustment disorder, study related with aging and phrenoblabia, anorexia nervosa, it is apathy, by generally curing Distractibility disease caused by condition, distractibility hyperactivity, conduct disorder (is included in that weaken related illness with cognitive power (such as dull-witted, mental retardation or delirium) in excitement), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, behavior disorder, cyclothymic disorder, depression, fibromyalgia (fibromyalgia) and other somatoform disorders, generalized-anxiety disorder, inhalation disorder, nosotoxicosis, dyskinesia (such as Huntington's disease or tardive dyskinesia), oppositional defiant disorder (oppositionaldefiant disorder), peripheral neurophaty, post-traumatic stress disorder, premenstruum (premenstrua) anxiety disorder, mental disease (short and long duration obstacle (brief and lo Ng durationdisorders), mental disease, psychotic disease NOS as caused by medical condition), mood disorder (major depression or bipolar disorder with psychotic features), Seasonal Affective sexual dysfunction, sleep disturbance, cognitive disorder, irritable bowel syndrome, specific developmental disorder, exciting disease, selective serotonin reuptake inhibit (SSRI) " tired " (" poop out ") syndrome or Tic disease (such as Tourette's syndrome).
The present invention further provides the method for treating anxiety or with nervous related obstacle, formula III compound or its pharmaceutically acceptable salt comprising giving mammal therapeutically effective amount.
The present invention further provides the method for treating depression, formula III compound or its pharmaceutically acceptable salt comprising giving mammal therapeutically effective amount.
The present invention further provides for treating fat method, formula III compound or its pharmaceutically acceptable salt comprising giving mammal therapeutically effective amount.
The present invention further provides the purposes that formula III compound or its pharmaceutically acceptable salt prepare drug, the drug is for treating or preventing central nervous system disease or obstacle.
The present invention further provides the compositions of compound of formula I and pharmaceutically acceptable carrier.
The present invention further provides the compositions of Formula II compound and pharmaceutically acceptable carrier.
The present invention can be provided for the novel intermediates and method of preparation formula III compound.
Detailed description of the invention
The compound of the present invention is named generally according to IUPAC or CAS naming system.Abbreviation well known within the skill of those ordinarily skilled (such as " Ph " represents phenyl, and " Me " represents methyl, and " Et " represents ethyl, and " h " represents hour, and " rt " represents room temperature etc.) can be used.
The carbon content of various hydrocarbonaceous parts indicates with the prefix for indicating minimum and maximum carbon atom number in the part, i.e. prefix Ci-jIndicate integer " i " to the part of a (containing endpoint) carbon atom of integer " j ".Thus, for example, C1-7Alkyl refers to the alkyl of one to seven (containing endpoint) carbon atom.
The following specific and preferred value about atomic group, group, part, substituent group or range is only for illustrating；They are not excluded for the other values in other defined values or defined range.
Using following definition, except being described elsewhere.
Term " halogen " indicates fluorine, chlorine, bromine or iodine.
Alkyl means straight and branched group；But straight chain group or part are only covered to separate base or partial reference, such as " propyl ", and branched isomer such as " isopropyl " then needs specifically to quote.
Aryl indicates bicyclic carbocyclic group or the part of phenyl radical or ortho-condensed, has about nine to ten annular atoms, wherein at least one ring is armaticity.
Mammal indicates humans and animals.
It is understood that the present invention covers or mixtures thereof any racemic, optically active, polymorphous, tautomeric or stereomeric form of the compounds of this invention, they have useful quality as described herein.
Compound be enough alkalinity or it is acid to generate suitable nontoxic acid or alkali salt in the case where, compound be administered in a salt form can be it is appropriate.The example of pharmaceutically acceptable salt is the acid organic acid addition salt generated with the physiologically acceptable anion of generation, such as tosilate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, maleate, fumarate, benzene sulfonate and α-glycerophosphate.Suitable inorganic salts, including hydrobromate, hydrochloride, sulfate, nitrate, bicarbonate and carbonate can also be generated.
Pharmaceutically acceptable salt can use standard technology well known in the art and obtain, such as react the compound such as amine of enough alkalinity with the suitable acid for providing physiologically acceptable anion.The alkali metal (such as sodium, potassium or lithium) or alkaline-earth metal (such as calcium) salt of carboxylic acid can also be prepared.
In one embodiment, R1It is H or C1-4Alkyl.
In another embodiment, R1It is methyl.
In one embodiment, R1It is H.
In another embodiment, each R2It is independently H or C1-6Alkyl.
In another embodiment, R2It is H.
In one embodiment, each R3It is independently H, fluorine or C1-4Alkyl.
In one embodiment, each R3It is fluorine, n is 1 or 2.
In one embodiment, each R5It is independently H or C1-4Alkyl.
In one embodiment, R5It is H.
In one embodiment, each R5It is independently H or C (=O) R1。
In one embodiment, each R5It is independently H or C (=O) RCH3。
In one embodiment, each R5It is independently H, S (O)2R1、C(O)NR1R1、CO2R1Or CSR1。
In one embodiment, R6It is H, methyl or ethyl.
In one embodiment, R7It is H.
In one embodiment, R8It is H or fluorine or methyl.
Example of the invention is:
(1) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl) phenyl amine,
(2) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl amine,
(3) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine,
(4) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl amine,
(5) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl]-N- aminomethyl phenyl amine,
(6) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(3- fluorophenyl) sulfonyl] aniline,
(7) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(3- fluorophenyl) sulfonyl] phenyl amine,
(8) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide,
(9) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide, or
(10) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide,
Or its pharmaceutically acceptable salt.
Other examples of the invention are:
(1) 2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine,
(2) 2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(3) 2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(4) 2- [(4- aminomethyl phenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(5) 2- [(4- aminomethyl phenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(6) 5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl amine,
(7) 2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine, or
(8) N- ethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine or its pharmaceutically acceptable salt.
Specific example of the invention is N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl] acetamide or its pharmaceutically acceptable salt.
Specific example of the invention is 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine or its pharmaceutically acceptable salt.
Specific example of the invention is N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide or its pharmaceutically acceptable salt.
Figure I and figure II describes the preparation of the compounds of this invention.All raw materials are all that will be prepared by processes described herein or for organic chemistry filed technique well-known to the ordinarily skilled artisan.As schemed shown in I, the required aryl mercaptan of commercially available substituted or unsubstituted 2,5- difluoro nitrobenzene 1 is handled, thioether 2 is obtained.The reaction usually carries out in the presence of suitable alkali and suitable solvent, alkali such as potassium carbonate, solvent such as acetonitrile.2 are oxidized to sulfone 3 usually using m-CPBA (CH2Cl2Solution) or H2O2(hot acetic acid solution) is used as oxidant.When using m-CPBA, reacts and be performed such, at ambient temperature, in a solvent, such as methylene chloride.Required aryl piperazines part 4 generates in this way, using amine appropriate, carries out second nucleophilic substitution reaction.This metathesis still uses potassium carbonate as alkali, solvent for use such as acetonitrile.Depending on R_ substituent group, nitrobenzene 4, which is reduced to aniline 5, to be completed using Raney nickel and hydrazine.The solvent system most often utilized is EtOH/THF.It is further purified if necessary to 5, then being t-butylcarbamate (THF, H with di-tert-butyl dicarbonic acid ester protection piperazine 42O), carbamate 6 is obtained.The compound is restored with Raney nickel as described above, obtains aniline 7.With compound 5 on the contrary, carbamate 7 can easily be purified with chromatography.In CH2Cl2It is middle to be deprotected with TFA, obtain bis sulfone 5.If necessary, carbamate 7 can be partially alkylated or alkylated, and obtain the compound of structure 8.In this case, 7 are handled in the presence of hydrofining with Methyl triflate, obtains methyl amine 8.As described above in CH2Cl2It is middle to be deprotected with TFA, obtain the compound of structure 5.
Alternatively, alkylated 5 compound of structure of N- can be prepared according to shown in figure II.2 compound of structure reacts (potassium carbonate/acetonitrile as described in figure I with required piperazine；Environment temperature is to high temperature), obtain piperazine 9.With di-tert-butyl dicarbonic acid ester protection 9, carbamate 10 is obtained.Nitro 10 is restored with Raney nickel and hydrazine, obtains aniline 11, it can be easy and excess acetyl chloride, obtains 12.The reaction carry out in this way be it is fairly effective, using chloroacetic chloride (or other acyl chlorides or Ethyl formate), in the presence of DMAP and Hunigs alkali, in suitable solvent, such as CH2Cl2.12 to be oxidized to sulfone be to complete (CH with m-CPBA2Cl2, -78 DEG C, to rt), obtain 13.Using boranemethylsulfide complex reducing amide 13, required alkylamine 14 is obtained.Piperazine is deprotected and is alkylated, the compound of structure 5 is obtained.If necessary, dialkylated compound can also be prepared according to method well known in the art.If necessary, it can will scheme the amide in II, such as 13 simply to be deprotected with the EthOH solution or TsOH of TFA, HCl, obtain 5 (R5=COCH of acetamide3).Sulfonamide can be prepared by similar manner.
Figure C0181067900181
Scheme I
Scheme II
Their native form or salt can be used in the compounds of this invention.In the case where compound is enough alkalinity or the acid nontoxic acid or alkali salt suitable with generation, it may be suitable for applying as the compound of salt.The example of pharmaceutically acceptable salt is the acid organic acid addition salt generated with the physiologically acceptable anion of generation, such as tosilate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate (etoglutarate) and glycerophosphate.Suitable inorganic salts, including hydrogen chlorate, sulfate, nitrate, bicarbonate and carbonate can also be generated.
Pharmaceutically acceptable salt can use standard technology well known in the art and obtain, such as react the compound such as amine of enough alkalinity with the suitable acid for providing physiologically acceptable anion.The alkali metal (such as sodium, potassium or lithium) or alkaline-earth metal (such as calcium) salt of carboxylic acid can also be prepared.
The compound of the present invention can be suitable for being administered in a manner of pharmaceutical composition, wherein the combination containing the compound and suitable excipient, the composition can be used for fighting CNS disease.The preparation method of pharmaceutical composition containing the compound for being applicable in CNS disease and contained excipient are well known in the art.The generally acknowledged summary of such methods and ingredient is Remington ' the s Pharmaceutical Sciences (RemingtonShi pharmaceutical science) (Mark Publ.Co., 15th Ed., 1975) of E.W.Martin.The compound of the present invention and the administration mode of composition can be parenteral (such as in intravenous, peritonaeum or intramuscular injection), part (including but not limited to surface treatment, Transdermal application and nose use), intravaginal, oral or rectal, this depends on whether preparation is used to treat specific disease.
About oral therapeutic administration, the dosage forms such as ingestible tablet, cheek piece, pastille, capsule, elixir, suspension, syrup, wafer can be used by reactive compound in conjunction with one or more of excipient.This kind of composition and preparation should contain at least 0.1% reactive compound.The percentage of composition and preparation can of course be different, and can be suitable between about 2 to about 60 weight % of given unit dosage form.Amount of the reactive compound in this kind of therapeutically useful composition be it is such, it is up to effective dosage level.
Tablet, pastille, pill, capsule etc. can also contain as follows: adhesive, such as bassora gum, Arabic gum, cornstarch or gelatin；Excipient, such as Dicalcium Phosphate；Disintegrating agent, such as cornstarch, potato starch, alginic acid etc.；Lubricant, such as magnesium stearate；And sweetener, such as sucrose, fructose, lactose or aspartame, or corrigent can be added, such as peppermint, wintergreen or cherry flavor enhancement.When unit dosage form is capsule, other than the above-mentioned type material, it can also contain liquid-carrier, such as vegetable oil or polyethylene glycol.Other a variety of materials, which can be used as coating, to be existed, or the physical form of modification solid unit dosage forms.For example, can be by the coating such as tablet, pill or capsule gelatin, wax, shellac or sugar.Syrup or elixir can containing reactive compound, the sucrose as sweetener or fructose, as methyl p-hydroxybenzoate and propyl ester, the stain and corrigent of preservative, such as cherry or orange flavor enhancement.Certainly, being arbitrarily used to prepare the material of any unit dosage form all should be pharmaceutically acceptable and substantially nontoxic under dosage.Furthermore it is possible to reactive compound is incorporated into the preparation and medical instrument of sustained release, such as the osmotic release type devices developed by AlzaCorporation, trade mark OROS.
Compound or composition can also be by being transfused or injecting via intravenous or Intraperitoneal medication.The solution of reactive compound or its salt in water can be prepared, nontoxic surfactant is optionally mixed with.Disperse system in glycerol, liquid macrogol, glycerol triacetate and its mixture and in the oil can also be prepared.Under ordinary conditions of storage and use, these preparations contain preservative, to prevent the growth of microorganism.
The pharmaceutical dosage form for being suitable for injecting or being transfused may include sterile aqueous solution or disperse system, or the sterile powder comprising active constituent, they are adapted to the extemporaneous preparation of sterile injection or infusible solutions or disperse system, are optionally encapsulated in liposome.In all cases, final dosage form should be sterile fluid, be stable under manufacture and storage requirement.Liquid-carrier or medium can be solvent or liquid dispersion medium, such as include water, ethyl alcohol, polyalcohol (such as glycerol, propylene glycol, liquid macrogol etc.), vegetable oil, nontoxic glyceride and its suitable mixture.Appropriate mobility can for example be kept in this way, formed liposome, kept required partial size in the case where disperse system or utilize surfactant.Various antibacterial agents and antifungal agent can prevent effect, such as p-hydroxybenzoate, methaform, phenol, sorbic acid, thimerosal of microorganism etc..It in many cases, include isotonic agent will be preferred, such as sugar, buffer or sodium chloride.By the way that the absorption of Injectable composition, such as aluminum monostearate and gelatin can be extended in the reagent composition for postponing to absorb.
Sterile Injectable solution can be prepared, and the desired amount of reactive compound and (as needed) other above-named various compositions are incorporated into solvent appropriate, then filtration sterilization.In the case where being used to prepare the sterile powder of sterile injectable solution, preferred preparation method is vacuum drying and Freeze Drying Technique, obtains the powder that active constituent adds any in addition required ingredient being present in preparatory sterilefiltered solutions.
About local administration, the compounds of this invention can apply respective pure form, that is to say, that they are liquid at this time.But, it will generally need to be combined into composition or preparation to percutaneous drug delivery with carrier acceptable in dermatology, carrier can be solid or liquid.
Useful solid carrier includes finely pulverized solid, such as talcum, clay, microcrystalline cellulose, silica, aluminium oxide etc..Useful liquid-carrier includes water, alcohol or glycol or water-alcohol/diol mixture, wherein the compounds of this invention of effective level can be dissolved or is dispersed with, optionally by nontoxic surfactant.Auxiliary agent, such as fragrance and other antimicrobial can be added, to optimize the property of given purpose.Gained liquid composition can be applied from absorption pad, for impregnating bandage and other dressing or being sprayed on disease sites using pump-type or aerosol sprayers.Thickener can also be used together with liquid-carrier, such as synthetic polymer, fatty acid, fatty acid salt and ester, fatty alcohol, modified cellulose or modified inorganic material, paste, gelling agent, ointment, the soap agent etc. that can be spread out are formed, the skin of user is directly applied to.
The example of useful dermatological compositions that can be used for discharging compound of formula I to skin is known in the art；For example, see (United States Patent (USP) No.4,608,392) such as Jacquet, Geria (United States Patent (USP) No.4,992,478), (the United States Patent (USP) No.4,559 such as Smith, and Wortzman (United States Patent (USP) No.4,820,508) 157).
The useful dosage of compound of formula I can by comparing they external activity with determined in vivo activity in an animal model.The method for the effective dose for being extrapolated to people from mouse and other animals is known in the art；For example, see United States Patent (USP) No.4,938,949.
Compound is suitable for being administered with unit dosage form；Such as every unit dosage form contains 1 to 1000mg, is suitable for 5 to 750mg, optimum 5 to 400mg active constituent.Required dosage can be suitable for single-dose or be administered multiple times by appropriate intervals, such as daily two, three, four parts or more sub- dosage.Sub- dosage itself can be further divided into a large amount of administrations being discontinuously loosely spaced；Such as repeatedly sucking or multiple instillation are intraocular from insufflator.
Composition can be via oral and extra-parenteral administration, dosage level is calculated according to free alkali, about 0.01 to 300mg/kg weight of mammal, it is preferred that 0.1 to 50mg/kg weight of mammal, more preferable 1.0 to 30mg/kg weight of mammal, unit dosage form can be used to people, be administered daily one to four time, every dosage unit 1 to 1000mg.
In general, concentration of the compound of formula I in liquid composition, such as lotion would be about 0.1-25wt%, preferably from about 0.5-10wt%.Concentration in semisolid or solid composite, such as gelling agent or pulvis would be about 0.1-5wt%, preferably from about 0.5-2.5wt%.
Compounds as disclosed herein and the accurate dosage regimen of composition will be necessary the judgement depending on the needs of treated individual, the type for the treatment of and process, medical worker.The compound of the present invention can be administered animal in need for the treatment of.In most occasions, animal will be the mankind, but also especially cover the treatment of domestic animal and pet within the scope of the invention.
In general, the compound of the present invention is 5-HT ligand.The compounds of this invention combines or acts on the ability of 5-HT receptor or selective binding or acts on the ability of specific 5-HT receptor subtype and can use in vitro and in vivo measuring method known in the art and measured.The term as used herein " selective binding " indicates that compound combines other hypotypes of at least 2 times, preferably at least 10 times, more preferably at least 50 times of the easy degree one or more of given 5-HT hypotype.Preferred the compounds of this invention selective binding one or more 5-HT receptor subtype.
The ability that the compounds of this invention serves as 5-HT receptor stimulating agent or antagonist also can use in vitro and in vivo measuring method known in the art and be measured.All embodiment compounds provided above are all 5-HT ligands, are had under 1 μM of concentration from the radiolabeled ability for trial body of one or more of 5-HT receptor subtype displacement > 50%.Technique for testing this metathesis be it is well known, as described below.
5-HT6Receptor Binding Assay
The growth of cell and the preparation of film
Contain cloning people 5-HT6The Hela cell of receptor be obtained from the David doctor R.Sibley laboratory of National Instituteof Health (Sibley, D.R.,J. Neurochemistry, (Journal of Neurochemistry) 66, 47-56,1996).Cell is grown in high glucose Dulbecco Modified Eagle Medium, it is wherein supplemented with L-Glutamine, 0.5% Sodium Pyruvate, 0.3% Pen .- Strep, 0.025%G-418 and 5%Gibco fetal calf serum, harvest is in cold phosphate buffered saline (PBS) after being paved with.
The intact cell harvested washed once in cold phosphate buffered saline (PBS).Cell forms precipitating, is resuspended in the cold 50mM Tris of 100ml, 5mM EDTA and 5mM EGTA, pH7.4.4 periods are homogenized with Vir Tishear generator, 30 seconds every time, setting value 50.The homogenized cell of institute is centrifuged 10 minutes at 700RPM (1000Xg), removes supernatant.Precipitating is resuspended in the above-mentioned buffer of 100ml, then homogenizes 2 periods.Then it homogenized cell will be centrifuged 10 minutes at 700RPM (1000Xg) again, and remove supernatant.Merge supernatant (200ml), is centrifuged 1 hour under 23,000RPM (80,000Xg) in Beckman Rotor (42.1Ti).Film precipitating is resuspended in 50-8-ml measurement buffer, wherein containing HEPES 20mM, MgCl2 10mM, NaCl 150mM, EDTA 1mM, pH7.4, with aliquot refrigerated storage at -70 DEG C.
5-HT 6 Receptor binding assay
The use of radioligand binding assay [3H]-lysergic acid diethylamine (LSD).What the measuring method was performed such, it is added in 96 hole sample plates of Wallac by appropriate diluted 11 μ l for sample sheet (measuring method uses the sample of 11 kinds of series of concentrations, each double), mixture of the SPA bead and film that are coated with WGA of 11 μ l radioligands and 178 μ l by washing in combination buffer.Plate is shaken about 5 minutes, is then cultivated 1 hour at room temperature.Then plate is packed into counting box, is counted in Wallac MicroBeta Trilux scintillation counter.
Binding constant (Ki) measurement
The test compound for distributing 11 kinds of serial dilutions utilizes PE/Cetus Pro/Pette pipette assay plate.After these dilutions, addition radioligand and the bead-membrane mixture prepared as described above.The cpm for specifically binding gained using GraphPad Prism 2.0 editions is fitted one-site binding model.Using Cheng-Prusoff equation by estimated IC50Value be converted into Ki value (Cheng, Y.C. etc., Biochem.Pharmacol(biochemistry and pharmacology),22, 3099-108,1973).It is as shown in table 1 from measuring method gained Ki value.
Table 1
5-HT6Receptor Binding Assay data
Embodiment No.     Ki(nM)
    1     2.6
    2     4.9
    3     31
    4     32
    5     23
    6     68
    7     3.6
    8     5.2
    9     79
    10     11
    11     11
    12     1.4
    13     2.7
    14     --
About the following example, it is better understood with the preparation of the compound of the present invention and they, embodiment is the elaboration to invention scope rather than limits.
The preparation of embodiment 1 2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine
Figure C0181067900251
The preparation of fluoro- 2- nitro -1- (thiophenyl) benzene of step 1:4-
2,5- difluoro nitrobenzene (1.0ml, 9.2mmol) is added to the mixture of benzenethiol (0.96ml, 9.3mmol) and potassium carbonate (1.4g, 10.1mmol) in 16ml anhydrous acetonitrile.Mixture is stirred overnight at rt.Water (30ml) and CH is added2Cl2, layering.Water-bearing layer CH2Cl2It extracts (3 × 25ml).Merge organic layer, through MgSO4It dries, filters, is concentrated.Recrystallized from EtOAc/ heptane, obtain 2.3g (99%) title compound, be solid, mp66-67 DEG C.
IR (drift) 1576,1526,1468,1344,1286,1269,1209,946,866,819,806,756,749,693,645cm-1；1H NMR (300MHz, CDCl3) δ 7.95,7.54-7.60,7.46-7.52,7.07-7.15,6.85；MS(EI)m/z 249(M+), 203,202,186,185,184,78,77.
The preparation of fluoro- 2- nitro -1- (benzenesulfonyl) benzene of step 2:4-
At -78 DEG C, to fluoro- 2- nitro -1- (thiophenyl) benzene (8.7g, 35mmol) of 4- and sodium bicarbonate (7.3g, 87mmol) in 260ml CH2Cl2In mixture be slowly added to the 110ml CH of 3- chlorine benzylhydroperoxide (15g, 87mmol)2Cl2Solution.Solution is stirred into 1h at -78 DEG C, rt is then warmed to, is stirred overnight.Make mixture in NaHCO3(200ml) and CH2Cl2It is distributed between (3 × 100ml).Merge organic layer, through MgSO4It dries, filters, is concentrated, obtains white solid.Recrystallized from EtOAc/ heptane, obtain 9.7g (99%) title compound, be solid, mp127-129 DEG C.
IR (drift) 1602,1590,1551,1371,1329,1318,1274,1227,1161,1083,881,811,752,728,685cm-1；1H NMR (300MHz, CDCl3) δ 8.37-8.43,7.92-8.00,7.43-7.70；MS(EI)m/z 281(M+), 200,188,186,170,97,93,77.
The preparation of step 3:1- [3- nitro -4- (benzenesulfonyl) phenyl] piperazine
The 35ml acetonitrile solution of fluoro- 2- nitro -1- (benzenesulfonyl) benzene (1.0g, 3.6mmol) of 4-, piperazine (0.37g, 4.3mmol) and potassium carbonate (0.79g, 5.7mmol) is stirred overnight under reflux.35ml water and CH is added to rt in cooling mixture2Cl2.Layering, water-bearing layer CH2Cl2It extracts (3 × 35ml).Merge organic layer, through MgSO4It dries, filters, is concentrated.Via flash column chromatography (15%MeOH/CH2Cl2), obtain 1.1g (92%) title compound, be solid, mp180-182 DEG C.
IR (drift) 1601,1536,1448,1367,1358,1303,1254,1153,1138,1085,1022,774,750,724,688cm-1；1H NMR (300MHz, CDCl3) δ 8.10,7.89-7.95,7.47-7.55,6.95-7.05,3.31-3.45,2.96-3.08,2.51；MS(EI)m/z 347(M+), 305,275,258,152,118,77.
The preparation of step 4:4- [3- nitro -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate
To 1- [3- nitro -4- (benzenesulfonyl) phenyl] piperazine (1.5g, 4.3mmol) and NaOH (0.38g, 9.5mmol) in 64ml 1: 1 THF: H2The 5ml THF solution of di-tert-butyl dicarbonic acid ester (1.0g, 4.7mmol) is added in solution in O solvent system.Solution is stirred into 16h at rt.Mixture is neutralized with 6N HCl, and 25ml EtOAc is added.Layering, water-bearing layer extract (3 × 25ml) with EtOAc.Merge organic layer, through MgSO4It dries, filters, is concentrated.Recrystallized from EtOAc/ hexane, obtain 1.7g (87%) title compound, be solid, mp190-191 DEG C.
IR (drift) 1690,1607,1544,1415,1362,1350,1322,1306,1290,1243,1177,1151,1138,748,688cm-1；1H NMR (300MHz, CDCl3) δ 8.13,7.89-7.97,7.47-7.62,6.96-7.05,3.53-3.64,3.34-3.45,1.48；MS(EI)m/z 447(M+), 305,275,258,152,91,77.
The preparation of step 5:4- [3- amino -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate
To 4- [3- nitro -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate (0.85g; 1.8mmol) Raney nickel (the EtOH suspension of 130mg) is added in the solution in 4: 1 EtOH: THF solvent system of 20ml; then a hydrazine hydrate (0.44ml, 9.1mmol) is added.Mixture is vigorously stirred 2h, then by being filtered with the celite of water pretreatment.Filtrate is concentrated, it is white solid that residue crystallizes from MeOH/EtOAc/ hexane, obtains 0.76g (99%) aniline, mp135-137 DEG C.
IR (drift) 1693,1602,1552,1448,1420,1390,1366,1306,1288,1249,1224,1168,1142,1097,736cm-1；1H NMR (300MHz, CDCl3) δ 7.85-7.93,7.68,7.41-7.56,6.32,5.98,5.09,3.48-3.58,3.18-3.28,1.47；MS(EI)m/z417(M+), 361,317,275,167,91,77
The preparation of step 6:2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine
At 0 DEG C, to the 18ml CH of 4- [3- amino -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate (0.68g, 1.6mmol)2Cl2Trifluoroacetic acid (18ml) is added in solution.Solution is stirred into 2h at 0 DEG C, is then concentrated.CH is added2Cl2(30ml) and 1N NaOH (30ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 25ml), merges organic layer, through MgSO4It dries, filters, is concentrated, obtains 0.46g (89%) white solid.The solid is dissolved in 50ml MeOH, HCl/MeOH (5ml) is slowly added to, in N2Lower stirring 2min.Solvent is removed under vacuum, obtains white solid.Recrystallized from MeOH/EtOAc/ hexane, obtain pure title compound, be hydrogen chloride salt, mp165-166 DEG C.
IR (drift) 3371,2831,1600,1550,1447,1304,1284,1260,1225,1140,1092,1034,736,688,602cm-1；1H NMR (300MHz, CDCl3) δ 7.86-7.94,7.66,7.40-7.55,6.33,5.98,5.03,3.16-3.30,2.91-3.04,2.31；MS(EI)m/z 317(M+), 276,275,91,77.
The preparation of 2 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl amine
Make 1- [4- [(3- fluorophenyl) sulfonyl] -3- nitrobenzophenone] -1; 4- Diazesuberane (is prepared using with 1 step 3 process similarity of embodiment; 0.382g; 1.10mmol) hydrogen (25psi) is contacted in Parr bottles with the solution of Pd/C (0.0573g, 15wt%IV) in 4: 1 EtOH: THF solvent of 35ml.The pressure for monitoring hydrogen always, is maintained at 25psi or so.After 2h, mixture, solid MeOH and CH are filtered2Cl2It rinses, filtrate is concentrated, obtains 0.349g (99%) white solid.HCl salt is prepared with standard method, obtains pale solid.Recrystallized from hot MeOH/EtOAc/ hexane, obtain the title compound of almost quantitative yield, be hydrochloride, mp106-108 DEG C.
IR (drift) 1600,1550,1506,1474,1458,1313,1290,1270,1222,1135,1085,727,691,678,651cm-1；1H NMR (300MHz, CDCl3) δ 7.67-7.71,7.56-7.63,7.35-7.47,7.10-7.23,6.17,5.80,4.95,3.48-3.59,3.00,2.83,2.11,1.81-1.92；MS(EI)m/z349(M+), 307,293,281,148.
The preparation of 3 2- of embodiment [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine
In accordance with the common processes of embodiment 2, nonessential change is carried out, converts title compound, mp 144-146 DEG C for 2,5- difluoro nitrobenzene.
IR (drift) 2924,2919,2685,2676,2589,1599,1552,1492,1451,1286,1265,1236,1141,1092,601cm-1；1H NMR (300MHz, CDCl3) δ 7.83-7.91,7.64,7.03-7.12,6.69-6.74,6.23-6.30,3.46,3.06-3.15,2.81-2.89；MS(EI)m/z335(M+), 293,96,95,93,91,83
The preparation of 4 2- of embodiment [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine
Figure C0181067900282
In accordance with the common processes of embodiment 2, nonessential change is carried out, obtains title compound, mp 85-89 DEG C.
IR (drift) 2957,2926,2850,2828,2793,2714,1592,1552,1492,1450,1287,1238,1139,1090,837cm-1；1H NMR (300MHz, MeOH-d4) δ 8.30,7.64-7.75,7.37,7.04-7.12,3.36-3.44,2.54-2.62,2.36,1.67；MS(EI)m/z 349(M+), 334,279,213,120,96,91.
The preparation of 5 2- of embodiment [(4- aminomethyl phenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine
In accordance with the common processes of embodiment 1 (step 1-6), nonessential change is carried out, obtains title compound, mp 102-106 DEG C.
IR (drift) 1599,1551,1448,1302,1282,1262,1139,1092,812,728,705,680,671,667,657cm-1；1H NMR (300MHz, CDCl3) δ 7.77,7.66,7.20-7.30,6.31,5.97,5.09,3.17-3.30,2.93-3.03,2.37；MS(EI)m/z 331(M+), 290,289,119,93,92,91,65,57,56.
The preparation of 6 2- of embodiment [(4- aminomethyl phenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine
Figure C0181067900291
In accordance with the common processes of embodiment 1 (step 1-6), nonessential change is carried out, obtains title compound, mp 148-151 DEG C.
IR (drift) 3334,2954,2857,1598,1552,1453,1296,1288,1255,1140,1095,833,759,708,654cm-1；1H NMR (300MHz, CDCl3) δ 8.42-8.60,7.72-7.81,7.62-7.72,7.20-7.33,6.58,6.20-6.30,6.00,5.12,3.35-3.50,2.83,2.60,2.38；MS(EI)m/z345(M+), 330,120,92,91,71,65,58,57,56.
The preparation of 7 5- of embodiment (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl amine
In accordance with the common processes of embodiment 2, nonessential change is carried out, obtains title compound, mp 90-93 DEG C.
IR (drift) 3458,3370,2843,1601,1552,1448,1289,1264,1230,1140,1095,737,689,644,610cm-1；1H NMR (300MHz, CDCl3) δ 7.87-7.92,7.71,7.66,7.42-7.51,6.75,6.33,5.98,5.03,3.27-3.33,3.25-3.29,2.56-2.59,2.48-2.52,2.36,2.33；MS(EI)m/z 331(M+), 316,261,92,78.
The preparation of 8 2- of embodiment [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine
Figure C0181067900301
In accordance with the common processes of embodiment 2, nonessential change is carried out, obtains title compound, mp 89-92 DEG C.
IR (drift) 2670,2580,2467,2446,1601,1552,1474,1451,1293,1267,1222,1135,1087,697,616cm-1；1H NMR (300MHz, CDCl3) δ 7.30,7.11-7.19,6.82-6.86,6.68-6.78,6.38,6.31,4.24,3.20-3.28,2.55-2.59,2.36；MS(EI)m/z 349(M+), 334,279,91,86.
The preparation of 9 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl amine
Figure C0181067900302
In accordance with the common processes of embodiment 2, nonessential change is carried out, title compound is obtained.
MS (EI) m/z 367 (M+), 311,299,134,122,119,91,70,65,63,57.
The preparation of 10 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine
Figure C0181067900303
In accordance with the common processes of embodiment 2, nonessential change is carried out, but 1- [4- [(phenyl) sulfonyl] -3- nitrobenzophenone]-Isosorbide-5-Nitrae-Diazesuberane is used as raw material, to obtain title compound.
MS (FAB) m/z 332 (MH+), 486,408,348,334,333,332,331,330,191,44.
The preparation of 11 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl amine
Figure C0181067900304
In accordance with the common processes of embodiment 2, nonessential change is carried out, title compound is obtained.
MS (EI) m/z 367 (M+), 325,311,299,146,119,113,91,84,69,57.
The preparation of 12 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl]-N- aminomethyl phenyl amine
Figure C0181067900311
To 4- [3- amino -4- (benzenesulfonyl) phenyl] -5- (1; 4- Diazesuberane -1- base) -1- carboxylate (the preparation as described in 1 step 5 of embodiment; 2.3g; 5.1mmol) with Methyl triflate (0.58ml; 54ml anhydrous THF solution 5.1mmol) divides small lot that sodium hydride (0.21g, 5.1mmol) is added.After being added completely into, by mixture in N2It is stirred overnight under layer.55ml NH is added to solution4Cl makes to react all standing, layering.Water-bearing layer extracts (3 × 50ml) with EtOAc.Merge organic layer, through MgSO4It dries, filters, is concentrated.(30%EtOAc/ hexane) is purified via column chromatography, obtains required methylaniline.Carbamate is deprotected in accordance with the route of synthesis of 1 (step 6) of embodiment, obtains 0.11g (totally 6.0%) title compound, is solid.Recrystallized from MeOH/EtOAc/ hexane, obtain pure products, be HCl salt, mp153-154 DEG C.
IR (drift) 2944,2811,2734,2685,1596,1560,1468,1290,1270,1220,1133,795,732,691,677cm-1；1H NMR (300MHz, CDCl3) δ 7.45-7.65,7.34-7.45,7.12-7.21,6.15-6.30,6.10,5.72,3.51-3.60,3.30-3.44,3.01,2.81,2.27,1.80-1.91；MS(EI)m/z 363(M+), 307,295,234,216,146,81,77.
The preparation of embodiment 13 N- ethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine
The preparation of step 1:1- [3- nitro -4- (thiophenyl) phenyl] piperazine
Fluoro- 2- nitro -1- (thiophenyl) benzene of 4- (2, embodiment 1, step 1,2.7g, 9.5mmol) are added to the mixture of piperazine (1.0g, 12mmol) and potassium carbonate (2.0g, 14mmol) in 80ml anhydrous acetonitrile.Mixture is stirred overnight at rt.Water and CH is added2Cl2(each 80ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 50ml).Merge organic layer, through MgSO4It dries, filters, is concentrated.1.6g (47%) title compound is obtained via column chromatography purifying (50%EtOAc/ hexane), for red oil.
IR (drift) 3683,3020,2400,1547,1521,1441,1338,1295,1215,851,758,754,707,692,669cm-1；1H NMR (300MHz, CDCl3) δ 7.63,7.35-7.60,6.90-7.00,6.81-6.96,3.16-3.23,3.02-3.08；MS(EI)m/z 315(M+), 273,243,226,184,139,84,77.
The preparation of step 2:4- [3- nitro -4- (thiophenyl) phenyl] -1- piperazinecarboxylate
To 1- [3- nitro -4- (thiophenyl) phenyl] piperazine (1.6g, 4.5mmol) and NaOH (0.39g, 9.8mmol) in 64ml 1: 1 THF: H2The 5ml THF solution of di-tert-butyl dicarbonic acid ester (1.1g, 4.9mmol) is added in solution in O solvent system.Solution is stirred into 16h at rt.It is in neutrality mixture with 6N HCl, 25ml EtOAc is added.Layering, water-bearing layer extract (3 × 25ml) with EtOAc.Merge organic layer, through MgSO4It dries, filters, is concentrated.(15%EtOAc/ hexane) is purified by column chromatography, obtains 1.7g (85%) title compound, for oil.
IR (drift) 3437,3344,2976,1682,1613,1595,1501,1429,1365,1290,1258,1221,1165,1128,733cm-1；1H NMR (300MHz, CDCl3) δ 7.66,7.49-7.57,7.39-7.47,6.98,6.85,3.56-3.64,3.13-3.23,1.50；MS(EI)m/z 415(M+), 385,329,285,244,243,227,151.
The preparation of step 3:4- [3- amino -4- (thiophenyl) phenyl] -1- piperazinecarboxylate
To 4- [3- nitro -4- (thiophenyl) phenyl] -1- piperazinecarboxylate (1.7g, 3.8mmol) Raney nickel (the EtOH suspension of 260mg) is added in the solution in 4: 1 EtOH: THF solvent system of 42ml, then a hydrazine hydrate (0.92ml, 19mmol) is added.Mixture is vigorously stirred 2h, then by being filtered with the celite of water pretreatment.Filtrate is concentrated, residue is crystallized from MeOH/EtOAc/ hexane, obtains 1.5g (92%) aniline, is white foam.
IR (drift) 3344,2976,1682,1613,1595,1501,1430,1365,1290,1259,1221,1166,766,733,687cm-1；1H NMR (300MHz, CDCl3) δ 7.34,7.16-7.24,7.02-7.11,6.30-6.41,4.34,3.54-3.64,3.15-3.24,1.49；MS(EI)m/z 385(MH+), 285,244,243,229,227,151,104.
The preparation of step 4:4- [3- (acetylamino) -4- (thiophenyl) phenyl] -1- piperazinecarboxylate
By the anhydrous CH of 7ml of 4- [3- amino -4- (thiophenyl) phenyl] -1- piperazinecarboxylate (0.69g, 1.6mmol)2Cl2Solution is cooled to 0 DEG C.Chloroacetic chloride (0.13ml, 1.8mmol), diisopropylethylamine (0.32ml, 1.8mmol) and DMAP (0.020g, 0.16mmol) is added, so that solution is warmed to rt, is stirred overnight.Water and CH is added2Cl2(each 10ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 10ml), merges organic layer, with 1N HCl, H2O and salt water washing.Through MgSO4After drying, mixture is filtered, is concentrated, obtains crude product.(25%EtOAc/ hexane) is purified by column chromatography, obtains 0.70g (99%) title compound, for oil.
IR (mull) 1694,1596,1582,1557,1518,1440,1430,1395,1294,1271,1238,1179,1120,744,739cm-1；1H NMR (300MHz, CDCl3) δ 8.22-8.26,8.20,7.46,7.19-7.26,7.10-7.15,7.01-7.03,6.68,3.56-3.61,3.25-3.29,2.05,1.48；MS(EI)m/z427(M+), 371,327,285,227,218,161,147,134.
The preparation of step 5:4- [3- (acetylamino) -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate
To 4- [3- (acetylamino) -4- (thiophenyl) the phenyl] -1- piperazinecarboxylate (1.3g, 3.1mmol) and NaHCO for being cooled to -78 DEG C3(0.65g, 7.7mmol) is in 36mlCH2Cl2In mixture be added 3- chlorine benzylhydroperoxide (1.3g, 7.7mmol) in 17ml CH2Cl2In mixture.Solution is stirred into 1h at -78 DEG C, is then warmed to rt, is stirred other 6 hours.Make mixture in NaHCO3(50ml) and CH2Cl2It is distributed between (3 × 50ml), through MgSO4It dries, filters, is concentrated.(10%MeOH/CH is purified by column chromatography2Cl2), 0.51g (36%) pure title compound is obtained, is solid, mp 129-130 DEG C.
IR (drift) 1697,1592,1461,1442,1418,1393,1366,1287,1264,1252,1174,1149,1036,752,690cm-1；1H NMR (300MHz, CDCl3) δ 10.48,8.70-8.75,8.26,7.70,7.44-7.56,3.84-4.24,3.60-3.83,3.41,3.08-3.18,2.11；MS(EI)m/z 459(M+), 310,261,218,185,161,150,128,85,77.
The preparation of step 6:4- [3- (ethylamino) -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate
To 4- [3- (acetylamino) -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate (0.44g; 0.96mmol) boranemethylsulfide complex (0.28ml is added in the mixture in the anhydrous THF of 7ml; 2.8mmol, 10.0M).Mixture is stirred overnight at rt.10%HCl, which is added dropwise, to be made to react all standing.Water (3.0ml) and KOH (2.0g) is added, mixture is heated into 6h under reflux.Methanol (2ml) is added at this time, mixture is stirred overnight under reflux.After being cooled to rt, organic layer is removed under reduced pressure, and water-bearing layer is saturated with NaCl, uses CH2Cl2It extracts (3 × 10ml).Merge organic layer, through MgSO4It dries, filters, is concentrated, obtains crude product.(15%EtOAc/ hexane) is purified by column chromatography, obtains 0.18g (43%) pure title compound, for oil.
IR (drift) 2970,1690,1592,1561,1476,1457,1430,1363,1288,1243,1215,1173,1128,993,743cm-1；1H NMR (300MHz, CDCl3) δ 7.48-7.55,7.36-7.46,7.32,6.20,5.96,5.90,3.49-3.59,3.17-3.25,2.82-3.06,1.47,1.05；MS (EI) m/z 445 (M+), 414,357,324,280,271,147,136,104,58,57.
The preparation of step 7:N- ethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine
At 0 DEG C, to the 4.6ml CH of 4- [3- (ethylamino) -4- (benzenesulfonyl) phenyl] -1- piperazinecarboxylate (0.18g, 0.40mmol)2Cl2Trifluoroacetic acid (4.6ml) is added in solution.Solution is stirred into 2h at 0 DEG C, is then concentrated.CH is added2Cl2(10ml) and 1N NaOH (10ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 15ml), merges organic layer, through MgSO4It dries, filters, is concentrated, obtains 0.13g (86%) white solid.The solid is dissolved in 25ml MeOH, is slowly added to HCl/MeOH (5ml).Solvent is removed under vacuum, obtains white solid.It is recrystallized from MeOH/EtOAc/ hexane, obtains pure title compound, be hydrogen chloride salt, mp 121-123 DEG C.
IR (drift) 2957,2932,2822,2778,2747,2720,2692,1599,1588,1566,1512,1449,1440,1220,739cm-1；1H NMR (300MHz, CDCl3) δ 7.36,7.17-7.25,7.03-7.12,6.30,6.20,4.77-4.85,3.22-3.29,3.11-3.22,3.03-3.10,2.00,1.18；MS(EI)m/z345(M+), 313,271,147,136,133,117,91,77.
The preparation of 14 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(3- fluorophenyl) sulfonyl] anilinechloride
Figure C0181067900351
In accordance with the common processes of embodiment 13 (step 1-7), nonessential change is carried out, converts title compound for 1- [the fluoro- 2- nitro -1- (thiophenyl) of 4-] -3- fluorobenzene (preparation as described in 1 step 1 of embodiment).
MS (EI) m/z 377 (M+), 321,310,309,135,131,119,117,83,77,69.
The preparation of 15 N- of embodiment [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl] acetamide and its mesylate
The fluoro- 2- nitrobenzophenone 3- fluorophenyl magister of sulfur of step 1:4-
2,5- difluoro nitrobenzene (7.00ml, 64.55mmol) is added to the mixture of 3- fluoro thiophenol (8.36g, 65.2mmol) and potassium carbonate (9.81g, 71.0mmol) in 115ml anhydrous acetonitrile.Mixture is stirred at room temperature 2 hours.Water and CH is added2Cl2(each 120ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 50ml).Merge organic layer, through MgSO4It dries, filters, is concentrated, obtains bright yellow solid.The solid is developed with hexane, obtains 17.1g (99%) title compound, is bright yellow solid.
1H NMR (300MHz, CDCl3) δ 7.95,7.41-7.51,7.33-7.38,7.26-7.31,7.12-7.24,6.91.
The preparation of the fluoro- 2- nitrobenzophenone 3- fluorophenyl sulfone of step 2:4-
Mixture of the fluoro- 2- nitrobenzophenone 3- fluorophenyl sulphur (17.1g, 64.1mmol) of 4- in 430ml glacial acetic acid is heated to 100 DEG C, with 7.4ml 30%H2O2Solution processing.After stirring 20min at 100 DEG C, another 7.4ml H is added2O2Mixture is stirred other 30min by solution at 100 DEG C.After being cooled to room temperature, mixture is diluted with 450ml water, filtering gained white solid.Solid is rinsed with 1N NaOH and water, is white solid until with hexane development, being dried under vacuum to the aobvious neutrality of reindeer moss, obtaining 18.5g (96%) title compound.
1H NMR (300MHz, CDCl3) δ 8.38-8.43,7.74-7.77,7.62-7.66,7.47-7.60,7.31-7.48.
The preparation of step 3:4- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- nitrobenzophenone 3- fluorophenyl sulfone
By the fluoro- 2- nitrobenzophenone 3- fluorophenyl sulfone (5.00g of 4-, 16.7mmol), homopiperazine (2.09g, 20.9mmol) 4h is vigorously stirred at 60 DEG C in the mixture in 140ml anhydrous acetonitrile with potassium carbonate (3.46g, 25.1mmol).After being cooled to room temperature, water and CH is added2Cl2(each 140ml), layering.Water-bearing layer CH2Cl2It extracts (3 × 50ml).Merge organic layer, through MgSO4It dries, filters, is concentrated, obtains orange solids.By crude product with hot Et2O∶CH2Cl2Mixture (4: 1) is developed into solid.Further with hot EtOAc/ hexane development, 6.31g (99%) title compound is obtained, is bright yellow solid.
1H NMR (300MHz, CDCl3) δ 8.05,7.71-7.76,7.59-7.64,7.46-7.54,7.22-7.30,6.90,6.83,3.54-3.70,3.00-3.07,2.80-2.88,1.82-1.94.
Step 4:4- [4- [(3- fluorophenyl) sulfonyl] -3- nitrobenzophenone]-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylate preparation
To 4- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- nitrobenzophenone 3- fluorophenyl sulfone (49.1g, 129mmol) and sodium hydroxide (11.4g, 286mmol) in 650ml 1: 1 THF: H2Mixture in O solvent is slowly added to mixture of the di-tert-butyl dicarbonic acid ester (32.4g, 148mmol) in 5ml THF.Solution is stirred into 16h at rt.With in 6N HCl and mixture, 200ml CH is added2Cl2.Layering, water-bearing layer CH2Cl2It extracts (3 × 100ml).Merge organic layer, through MgSO4It dries, filters, is concentrated, obtains orange solids.By crude product EtOAc and hexane development, 60.35g (99%) title compound is obtained, is bright yellow solid.
1H NMR (400MHz, CDCl3) δ 8.12,7.76-7.80,7.63-7.67,7.52-7.58,7.31-7.34,6.94-6.97,6.87-6.92,3.62-3.75,3.39-3.45,3.30-3.35,1.94-2.03,1.42,1.34.
Step 5:4- [3- amino -4- [(3- fluorophenyl) sulfonyl] phenyl-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylate preparation
Make 4- { 4- [(3- fluorophenyl) sulfonyl] -3- nitrobenzophenone } -1; 4- Diazesuberane -1- carboxylate (58.0g; 121mmol) hydrogen (25psi) is contacted in Parr bottles with the mixture of Pd/C (8.70g, 15wt%) in 1.5L2: 1: 1 THF: MeOH: EtOH solvent.The pressure for monitoring hydrogen always, is maintained at 25psi or so.After 16h, mixture, solid MeOH and CH are filtered2Cl2It rinses, filtrate is concentrated, obtains brown solid.By the solid EtOAc and hexane development, 53.4g (98%) title compound is obtained, is pale solid.
1H NMR (400MHz, CDCl3) δ 7.72-7.76,7.64,7.44-7.51,7.21-7.27,6.22-7.26,5.84-5.87,5.03-5.09,3.52-3.63,3.33-3.38,3.23-3.29,1.91-1.99,1.45,1.34.
Step 6:4- [3- (acetylamino) -4- [(3- fluorophenyl) sulfonyl] phenyl]-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylate preparation
By 4- [3- amino -4- [(3- fluorophenyl) sulfonyl] phenyl] -1; the mixture of 4- Diazesuberane -1- carboxylate (0.29g, 0.66mmol) and anhydrous acetic acid acid anhydride (1.0ml) stir 1h under 60 DEG C and nitrogen atmosphere.After being cooled to rt, 5ml toluene is added, mixture is concentrated.By the more toluene of crude product, then use EtOAc and Et2O is developed, and obtains 0.31g (97%) title compound, is white solid.
1H NMR (400MHz, CDCl3) δ 9.50-9.66,7.78-7.85,7.67,7.51-7.54,7.37-7.45,7.14-7.19,6.35-6.44,3.50-3.58,3.21-3.27,3.12-3.17,2.15,1.86-1.94,1.33,1.28.
The preparation of step 7:N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl] acetamide methanesulfonate
To 4- [3- (acetylamino) -4- [(3- fluorophenyl) sulfonyl] phenyl]-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylate (0.508g, 1.03mmol) in 20ml 1: 1Et2O∶CH2Cl2Anhydrous methanesulfonic acid (0.109g, 1.14mmol) is added in mixture in solvent, and mixture is stirred 2.5 hours at rt.Hot Et is added2O (10ml) filters white solid, uses Et2O is rinsed, and is dried under vacuum, is obtained 0.497g (99%) title compound, is white solid.
1H NMR (400MHz, DMSO-d6) δ 9.42,8.62-8.64,7.84,7.64-7.69,7.50-7.56,7.18-7.22,6.77,3.69-3.74,3.49-3.55,3.22-3.28,3.11-3.18,2.29,2.04-2.08,1.98-2.03.
The preparation of 16 5- of embodiment (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(3- fluorophenyl) sulfonyl] phenyl amine
In accordance with the common processes of embodiment 2, nonessential change is carried out, title compound is obtained.
MS(CI)m/z 406(MH+), 408,406,249,247,245,219,69,58,56,52.
The preparation of 17 N- of embodiment [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide
Figure C0181067900381
In accordance with the common processes of embodiment 15, nonessential change is carried out, but uses fluoro thiophenol as raw material, obtains title compound.
HRMS (FAB) calculated value C19H23N3O3S+H1374.1538 measured value 374.1515.
The preparation of 18 N- of embodiment [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide
Figure C0181067900382
In accordance with the common processes of embodiment 15, nonessential change is carried out, title compound is obtained.
HRMS (FAB) calculated value C20H24FN3O3S+H1406.1600 measured value 406.1602.
The preparation of 19 N- of embodiment [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide
Figure C0181067900383
In accordance with the common processes of embodiment 15, nonessential change is carried out, title compound is obtained.
HRMS (FAB) calculated value C21H26FN3O3S+H1420.1757 measured value 420.1760.
In accordance with the common processes of embodiment 1-19, nonessential change, available following compounds are carried out.The example of these compounds is:
(1) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl] phenyl amine,
(2) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- methyl -2- (benzenesulfonyl) phenyl amine,
(3) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl]-N- aminomethyl phenyl amine,
(4) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl]-N- aminomethyl phenyl amine,
(5) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl]-N- aminomethyl phenyl amine,
(6) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- (benzenesulfonyl) phenyl amine,
(7) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(4- fluorophenyl) sulfonyl] phenyl amine,
(8) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(3,4- difluorophenyl) sulfonyl] phenyl amine,
(9) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(3,5- difluorophenyl) sulfonyl] phenyl amine,
(10) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl)-N- propyl phenyl amine,
(11) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl]-N- propyl phenyl amine,
(12) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl]-N- propyl phenyl amine,
(13) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl]-N- propyl phenyl amine,
(14) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl]-N- propyl phenyl amine,
(15) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- dimethyl -2- (benzenesulfonyl) phenyl amine,
(16) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl]-N, N- 3,5-dimethylphenyl amine,
(17) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl]-N, N- 3,5-dimethylphenyl amine,
(18) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl]-N, N- 3,5-dimethylphenyl amine,
(19) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl]-N, N- 3,5-dimethylphenyl amine,
(20) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- (benzenesulfonyl) phenyl amine,
(21) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(4- fluorophenyl) sulfonyl] phenyl amine,
(22) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(3,4- difluorophenyl) sulfonyl] phenyl amine,
(23) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(3,5- difluorophenyl) sulfonyl] phenyl amine,
(24) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl)-N, N- dipropyl phenyl amine,
(25) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl)-N, N- dipropyl phenyl amine,
(26) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl)-N, N- dipropyl phenyl amine,
(27) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl]-N, N- dipropyl phenyl amine, or
(28) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl]-N, N- dipropyl phenyl amine.
Other examples are:
(1) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl] phenyl] acetamide,
(2) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl] acetamide,
(3) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl] acetamide,
(4) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N- methylacetamide,
(5) N- { 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl }-N- methylacetamide,
(6) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl] phenyl]-N- methylacetamide,
(7) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl]-N- methylacetamide,
(8) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl]-N- methylacetamide,
(9) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N- ethyl acetamide,
(10) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide,
(11) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide,
(12) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide,
(13) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N- propyl acetamide,
(14) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl]-N- propyl acetamide,
(15) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(4- fluorophenyl) sulfonyl] phenyl]-N- propyl acetamide,
(16) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl-N- propyl acetamide,
(17) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl]-N- propyl acetamide,
(18) N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide,
(19) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base)-phenyl] acetamide,
(20) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(21) N- [2- [(3,5- difluorophenyl) sulfonyl -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(22) N- methyl-N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide,
(23) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methylacetamide,
(24) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methylacetamide,
(25) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methylacetamide,
(26) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methylacetamide,
(27) N- ethyl-N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl-acetamides,
(28) N- ethyl-N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(29) N- ethyl-N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(30) N- ethyl-N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(31) N- ethyl-N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide,
(32) N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N- propyl acetamide,
(33) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl acetamide,
(34) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl acetamide,
(35) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl acetamide,
(36) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl acetamide.
Other examples are:
(1) 5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine,
(2) 2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl amine,
(3) 2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl amine,
(4) 2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl amine,
(5) 2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl amine,
(6) N- methyl-N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] amine,
(7) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methyl amine,
(8) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methyl amine,
(9) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methyl amine,
(10) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- methyl amine,
(11) N- ethyl-N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] amine,
(12) N- ethyl-N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(13) N- ethyl-N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(14) N- ethyl-N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(15) N- ethyl-N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(16) N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N- propyl amine,
(17) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl amine,
(18) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl amine,
(19) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl amine,
(20) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N- propyl amine,
(21) N, N- dimethyl-N-[5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] amine,
(22) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dimethyl amine,
(23) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dimethyl amine,
(24) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dimethyl amine,
(25) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dimethyl amine,
(26) N, N- diethyl-N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] amine,
(27) N, N- diethyl-N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(28) N, N- diethyl-N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(29) N, N- diethyl-N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(30) N, N- diethyl-N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] amine,
(31) N- [5- (4- methyl-1,4- Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl]-N, N- dipropylamine,
(32) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dipropylamine,
(33) N- [2- [(4- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dipropylamine,
(34) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl]-N, N- dipropylamine, or
(35) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl-N, N- dipropylamine.
Separately-a little example is:
(1) 2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(2) 2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(3) 2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(4) N- methyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine,
(5) 2- [(3- fluorophenyl) sulfonyl]-N- methyl -5- (1- piperazinyl) phenyl amine,
(6) 2- [(3,4- difluorophenyl) sulfonyl]-N- methyl -5- (1- piperazinyl) phenyl amine,
(7) 2- [(3,5- difluorophenyl) sulfonyl]-N- methyl -5- (1- piperazinyl) phenyl amine,
(8) N- ethyl -2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(9) N- ethyl -2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(10) N- ethyl -2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(11) 2- (benzenesulfonyl) -5- (1- piperazinyl)-N- propyl phenyl amine,
(12) 2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl)-N- propyl phenyl amine,
(13) 2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl)-N- propyl phenyl amine,
(14) 2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl)-N- propyl phenyl amine,
(15) 2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl)-N- propyl phenyl amine,
(16) N, N- dimethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine,
(17) 2- [(3- fluorophenyl) sulfonyl]-N, N- dimethyl -5- (1- piperazinyl) phenyl amine,
(18) 2- [(4- fluorophenyl) sulfonyl]-N, N- dimethyl -5- (1- piperazinyl) phenyl amine,
(19) 2- [(3,4- difluorophenyl) sulfonyl]-N, N- dimethyl -5- (1- piperazinyl) phenyl amine,
(20) 2- [(3,5- difluorophenyl) sulfonyl]-N, N- dimethyl -5- (1- piperazinyl) phenyl amine,
(21) N, N- diethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine,
(22) N, N- diethyl -2 [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(23) N, N- diethyl -2 [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(24) N, N- diethyl -2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(25) N, N- diethyl -2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(26) 2- (benzenesulfonyl) -5- (1- piperazinyl)-N, N- dipropyl phenyl amine,
(27) 2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl)-N, N- dipropyl phenyl amine,
(28) 2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl)-N, N- dipropyl phenyl amine,
(29) 2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl)-N, N- dipropyl phenyl amine, or
(30) 2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl)-N, N- dipropyl phenyl amine.
Other examples are:
(1) N- [2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl] acetamide,
(2) N- [2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(3) N- [2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(4) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(5) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(6) N- methyl-N- [2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl] acetamide,
(7) N- [2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- methylacetamide,
(8) N- [2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- methylacetamide,
(9) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- methylacetamide,
(10) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- methylacetamide,
(11) N- ethyl-N- [2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl] acetamide,
(12) N- ethyl-N- [2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(13) N- ethyl-N- [2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(14) N- ethyl-N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(15) N- ethyl-N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl] acetamide,
(16) N- [2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl]-N- propyl acetamide,
(17) N- [2- [(3- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- propyl acetamide,
(18) N- [2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- propyl acetamide,
(19) N- [2- [(3,4- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- propyl acetamide,
(20) N- [2- [(3,5- difluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl]-N- propyl acetamide,
(21) N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] acetamide,
(22) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(23) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(24) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(25) N- [2- [(3,5- difluorophenyl) sulfonyl-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(26) N- methyl-N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] acetamide,
(27) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methylacetamide,
(28) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methylacetamide,
(29) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methylacetamide,
(30) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methylacetamide,
(31) N- ethyl-N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] acetamide,
(32) N- ethyl-N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(33) N- ethyl-N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] acetamide,
(34) N- ethyl-N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- ethyl acetamide,
(35) N- ethyl-N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-(36) piperazinyl) phenyl] acetamide,
(36) N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl]-N- propyl acetamide,
(37) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl acetamide,
(38) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl acetamide,
(39) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl acetamide, or
(40) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl acetamide.
Other examples are:
(1) 2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(2) 2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(3) N- methyl-N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] amine,
(4) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methyl amine,
(5) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methyl amine,
(6) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methyl amine,
(7) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- methyl amine,
(8) N- ethyl-N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] amine,
(9) N- ethyl-N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(10) N- ethyl-N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(11) N- ethyl-N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(12) N- ethyl-N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(13) N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl]-N- propyl amine,
(14) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl amine,
(15) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl amine,
(16) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl amine,
(17) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N- propyl amine,
(18) N, N- dimethyl-N-[5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] amine,
(19) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dimethyl amine,
(20) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dimethyl amine,
(21) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dimethyl amine,
(22) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dimethyl amine,
(23) N, N- diethyl-N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl] amine,
(24) N, N- dimethyl-N-[2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(25) N, N- diethyl-N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(26) N, N- diethyl-N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(27) N, N- diethyl-N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl] amine,
(28) N- [5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl]-N, N- dipropylamine,
(29) N- [2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dipropylamine,
(30) N- [2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dipropylamine,
(31) N- [2- [(3,4- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl]-N, N- dipropylamine, or
(32) N- [2- [(3,5- difluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl-N, N- dipropylamine.

Claims (41)

1, compound of formula I:
Figure C018106790002C1
Or its pharmaceutically acceptable salt, wherein
R1It is
A) H, or
b)C1-12Alkyl,
At each occurrence, R2It is independently
A) H,
At each occurrence, R3It is independently
A) H, or
b)R4；
R4It is
A) halogen,
At each occurrence, R5It is independently
A) H,
b)C1-6Alkyl, or
C) C (=O) R1,
At each occurrence, alkyl is optionally by one or more R4Replace；
M is 1,2 or 3；With
N is 1,2,3,4 or 5.
2, compound according to claim 1, wherein R1It is hydrogen or C1-4Alkyl.
3, compound according to claim 2, wherein R5It is H.
4, compound according to claim 2, wherein R5First is that H, the other is C1-4Alkyl.
5, compound according to claim 2, wherein R5First is that H, the other is C (=O) CH3。
6, according to the compound of claim 3,4 or 5, wherein R3It is hydrogen.
7, according to the compound of claim 3,4 or 5, wherein R3It is fluorine, n is 1 or 2.
8, according to the compound of claim 3,4 or 5, wherein R1It is hydrogen.
9, Formula II compound:
Figure C018106790003C1
Or its pharmaceutically acceptable salt, wherein
R6It is H or C1-4Alkyl；
R7It is H；
R8It is H, halogen or C1-4Alkyl；
R9It is H, C1-4Alkyl.
10, compound according to claim 9, wherein R6It is hydrogen.
11, compound according to claim 9, wherein R6It is methyl or ethyl.
12,0 or 11 compound according to claim 1, wherein R8It is hydrogen.
13,0 or 11 compound according to claim 1, wherein R8It is fluorine.
14,0 or 11 compound according to claim 1, wherein R8It is methyl.
15,0 or 11 compound according to claim 1, wherein each R9It is independently hydrogen, methyl or ethyl.
16, formula III compound or its pharmaceutically acceptable salt prepare the purposes of drug, and the drug is for treating mammalian central nervous system disease or obstacle
Wherein
R1It is
A) H, or
b)C1-12Alkyl,
At each occurrence, R2It is independently
A) H,
At each occurrence, R3It is independently
A) H,
b)C1-12Alkyl, or
c)R4；
R4It is
A) halogen,
At each occurrence, R5It is independently
A) H,
b)C1-6Alkyl, or
C) C (=O) R1,
At each occurrence, alkyl is optionally by one or more R4Replace；
K is 1 or 2；
M is 1,2 or 3；With
N is 1,2,3,4 or 5.
17, the purposes of claim 16, wherein R1It is H or C1-4Alkyl；R2It is H；R5It is H, C1-4Alkyl or COC1-4Alkyl；R3It is H, halogen or C1-4Alkyl.
18, the purposes of formula III compound or its pharmaceutically acceptable salt as defined in claim 16 in medicine preparation, the drug wherein involving 5-HT receptor, and need to adjust 5-HT function for treating mammalian diseases or obstacle.
19, the purposes of claim 18, wherein this receptor is 5-HT6Receptor.
20, the purposes of claim 16 or 18, wherein the mammal is people.
21, the purposes of claim 16 or 18, wherein the disease or obstacle are anxiety, depression, schizophrenia, related disease, panic disorder, terror, besetment and behavior disorder, post traumatic stress syndrome, immune system depression, major depression, mental disease, dementia paranoides, mania, convulsive disorders, personality disorder, migraine, drug habit, alcoholism, obesity, eating disorder or sleep disturbance with stress.
22, the purposes of claim 16 or 18, wherein the disease or obstacle are schizoid spirit, emotion, vegetalitas and psychomotor symptoms and the cone extracorporeal movement side effect of other antipsychotics.
23, the purposes of claim 16 or 18, wherein the disease is anxiety or the related disease with stress.
24, the purposes of claim 16 or 18, wherein the disease is fat.
25, the purposes of claim 16 or 18, wherein the disease is depression.
26, the purposes of claim 16 or 18, wherein the disease or obstacle are fat, depression, schizophrenia, schizophreniform disorder, Schizoaffective phrenoblabia, delusional disorder, with nervous related disease, panic disorder, it is terrified, besetment and behavior disorder, post traumatic stress syndrome, immune system depression, major depression, the uropoiesis that stress induces, stomach and intestine or cardiovascular system problem, neurodegeneration obstacle, autism, the vomiting of phase chemotherapy induced, hypertension, migraine, cluster headache, the sexual dysfunction of mammal, assuetude disturbance and abstinence syndrome, adjustment disorder, study related with aging and phrenoblabia, anorexia nervosa, it is apathy, the distractibility disease as caused by general medicine condition, distractibility hyperactivity, behavior Disorder, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, behavior disorder, cyclothymic disorder, depression, fibromyalgia and other somatoform disorders, generalized-anxiety disorder, inhalation disorder, nosotoxicosis, dyskinesia, oppositional defiant disorder, peripheral neurophaty, post-traumatic stress disorder, premenstruum (premenstrua) anxiety disorder, mental disease, mood disorder, Seasonal Affective sexual dysfunction, sleep disturbance, cognitive disorder, irritable bowel syndrome, specific developmental disorder, exciting disease, selective serotonin reuptake inhibits " tired " syndrome or Tourette's syndrome.
27, the purposes of claim 16 or 18, wherein the drug is per rectum, part, nose, sublingual, transdermal or parenteral modes of administration.
28, the purposes of claim 16 or 18, wherein the drug is oral administration.
29, the purposes of claim 16 or 18, wherein the dosage of the compound is daily from 0.01 to weight of mammal described in 300mg/kg.
30, the purposes of claim 29, wherein the dosage of the compound is daily from 0.1 to weight of mammal described in 50mg/kg.
31, the purposes of claim 29, wherein the dosage of the compound is daily from 1 to weight of mammal described in 30mg/kg.
32, the compound of claim 1, it is
(1) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl) phenyl amine,
(2) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,4- difluorophenyl) sulfonyl] phenyl amine,
(3) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine,
(4) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3,5- difluorophenyl) sulfonyl] phenyl amine,
(5) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl]-N- aminomethyl phenyl amine,
(6) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N- ethyl -2- [(3- fluorophenyl) sulfonyl] aniline,
(7) 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base)-N, N- diethyl -2- [(3- fluorophenyl) sulfonyl] phenyl amine,
(8) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide,
(9) N- [2- [(3- fluorophenyl) sulfonyl] -5- (4- methyl-1,4- Diazesuberane -1- base) phenyl] acetamide, or
(10) N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl]-N- ethyl acetamide.
33, the compound of claim 9, it is
(1) 2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine,
(2) 2- [(4- fluorophenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(3) 2- [(4- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(4) 2- [(4- aminomethyl phenyl) sulfonyl] -5- (1- piperazinyl) phenyl amine,
(5) 2- [(4- aminomethyl phenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine,
(6) 5- (4- methyl-1-piperazinyl)-2- (benzenesulfonyl) phenyl amine,
(7) 2- [(3- fluorophenyl) sulfonyl]-5- (4- methyl-1-piperazinyl) phenyl amine, or
(8) N- ethyl -2- (benzenesulfonyl) -5- (1- piperazinyl) phenyl amine.
34, the compound of claim 1 is selected from N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- [(3- fluorophenyl) sulfonyl] phenyl] acetamide or its pharmaceutically acceptable salt.
35, the compound of claim 1 is selected from 5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl amine or its pharmaceutically acceptable salt.
36, the compound of claim 1 is selected from N- [5- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- (benzenesulfonyl) phenyl] acetamide or its pharmaceutically acceptable salt.
37, pharmaceutically acceptable composition, compound and pharmaceutically acceptable carrier comprising claim 1.
38, pharmaceutically acceptable composition, compound and pharmaceutically acceptable carrier comprising claim 9.
39, the pharmaceutically acceptable composition of claim 37, compound and pharmaceutically acceptable carrier comprising claim 34.
40, the pharmaceutically acceptable composition of claim 37, compound and pharmaceutically acceptable carrier comprising claim 35.
41, the pharmaceutically acceptable composition of claim 37, compound and pharmaceutically acceptable carrier comprising claim 36.
CN01810679XA 2000-06-20 2001-06-08 Bis-arylsulfones Expired - Fee Related CN1217938C (en)

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